Little is known about the mechanisms regulating T cell homeostasis in primates. The overall aim of this project is to study the homeostatic regulation of T cells in healthy rhesus macaques (RM) and sooty mangabeys (SM) via antibody-induced depletion of specific T cell subsets. We believe that this proposal is relevant to AIDS research due to the specific features of SIV-infection in the two species, i.e. pathogenic in RM and non-pathogenic in SM. If our study identifies differences in T cell homeostasis between RM and SM, we may then hypothesize that these differences play a role in determining the clinical outcome after SIV-infection. In earlier studies we showed that although CD4+ T cells are lost due to the cytopathic effect of the virus during both pathogenic and non-pathogenic infections, only in pathogenic infections is the homeostasis of T cells lost. This observation suggests that the failure of T cell homeostasis may play a role in the pathogenesis of AIDS, and that treatments aimed at reconstituting this homeostasis may be used in the clinical management of HIV-infected patients. Here we propose to study the lymphocyte repopulation that follows CD4+ and CD8+ T cell depletion by sequentially sampling bone marrow (BM), peripheral blood (PB) and lymph nodes (LN). The performed analyses will include: (1) immunophenotypic studies, (2) determination of levels of recent thymic emigrants, and (3) examination of levels of cytokines, i.e. IL-7, IL-15and IL-2, that may play a role in T cell homeostasis. In this application we also propose to evaluate the role of the thymus in T cell homeostasis by performing CD4+ and CD8+ T cell depletions in both normal and thymectomized animals. We believe that this comparative study may provide information on (1) the differential role of BM, LN and thymus in T cell homeostasis; (2) the specific features of the homeostasis ofCD4+ and CD8+ T cells; (3) the immunophenotype of T cells that are proliferating via homeostatic mechanisms; and (4) the role of cytokines in reconstituting acutely depleted T cell populations. Importantly, this approach may allow us to define differences in the way T cell homeostasis is maintained in RM vs SM, which could provide clue regarding the markedly different impact of SIV-infection in the two species. In all, we believe that this project may provide useful information on the homeostasis of T cells in primates, and how the failure of this homeostasis may play a role in the pathogenesis of AIDS.